tbuckley/cabot-search huggingface dataset:
Outcomes of patients with T1a,b N0 Her2-positive breast cancer treated with adjuvant trastuzumab in a prospective registry in Ontario, Canada.
Authors: Andrea Eisen, Tripat Gill, Steven Habbous, Jaclyn M. Beca, Jessica Arias, Kelvin K. Chan, Maureen E. Trudeau
Journal: Journal of Clinical Oncology (2022)

533 Background: Multiple randomized trials of chemo +/- tras in early stage, Her 2 positive BrCa demonstrated improvement in survival, but patients (pts) with T1a,b N0 disease were mostly excluded. Given the uncertainty of benefit in this group and the toxicities of chemo + tras, treatment in Ontario was funded for these patients conditional upon data collection for toxicity and survival endpoints. We report the outcomes for 483 patients enrolled in this Evidence Building Program (EBP). Methods: Between 2011 and 2018, 483 eligible pts with Her 2 pos disease and adequate cardiac function were treated with chemo + tras in the EBP. Cardiac toxicity, febrile neutropenia (FN), event-free (EFS), and overall survival (OS) were determined for this cohort from administrative datasets, and compared retrospectively to controls of similar stage selected from the Ontario Cancer Registry who did not receive tras and/or chemo. For the EBP cohort, clinicians also reported changes in left ventricular ejection fraction (LVEF). Results: Pt characteristics are shown in the Table. EBP patients had improved OS when compared to controls who received no chemo or tras. The 3-year OS in the EBP pts was 99.1%, versus 96.9% in the controls [adjusted HR 0.59 (95% CI 0.29-1.20)]. Patients receiving EBP tras had a significantly longer EFS than controls with or without chemo [adjusted HR 0.54 (0.36-0.83), p=0.005]. Use of chemo + tras in EBP pts was associated with an increased risk of clinical congestive heart disease (CHD) and febrile neutropenia (FN). About 3.5% of pts experienced CHD during treatment with chemo + tras. About 6% of pts had an absolute reduction of LVEF &gt;10% or reached LVEF &lt;50%. In an adjusted analysis, the risk of CHD was higher in older pts [HR 1.06 (1.03-1.08) per 1-yr increase in age, p&lt;0.0001) and for pts who received anthracyclines [HR 5.00 (1.71-14.7). In a matched analysis, the crude frequency of FN during treatment was 20% in EBP pts vs. 3% among controls who did not receive chemo or tras (p&lt;0.001). Conclusions: Analysis of the Ontario EBP for pts with, T1a,b N0 HER2 pos BrCa revealed that the prognosis is excellent and is improved with the use of chemo + tras. The safety profile was expected and tolerable, especially when non anthracycline chemo was used. These results led to a funding policy change where prospective data collection has been discontinued and chemo + tras is now routinely funded in this population. [Table: see text]
Predictors of residual tumor at re-staging transurethral resection for high-risk non-muscle invasive bladder cancer: Insights from a large multi-institutional collaboration
Authors: F. Claps, N. Pavan, N. D'Altilia, E. Checcucci, L. Napolitano, A. Morlacco, A. Tafuri, C. Palumbo, L. Boeri, G. Tulone, C. Bignù, G. Liguori, G.M. Busetto, A. Simonato, E. Montanari, L. Carmignani, A. Celia, A. Volpe, A. Antonelli, F. Dal Moro, V. Mirone, F. Porpiglia, L. Cormio, G. Carrieri, C. Trombetta
Journal: European Urology (2022)
Characterization of bladder cancer patient-derived organoids and potential application for personalized medicine
Authors: M. Minoli, M. Kiener, T. Cantore, T. Fedrizzi, P. Gasperini, F. Demichelis, G.N. Thalmann, R. Seiler-Blarer, M. Kruithof-De Julio
Journal: European Urology (2022)
Clinical value of next-generation sequencing in endocrine therapy for advanced hormone receptor–positive/HER2-negative breast cancer.
Authors: Dan Lv, Binliang Liu, Bo Lan, Lixi Li, Xiaoying Sun, Fei Ma
Journal: Journal of Clinical Oncology (2022)

1062 Background: Acquired gene mutation is a major mechanism of resistance to endocrine therapy in hormone receptor (HR)-positive advanced breast cancer. Circulating tumor DNA (ctDNA) facilitates the current assessment of the genomic profile in patients with advanced cancer. We performed this clinical trial to determine the landscape of gene mutation before endocrine therapy, to search for molecular markers of endocrine therapy efficacy, and to explore the clinical value of ctDNA to guide precise endocrine therapy in patients with advanced breast cancer. Methods: We conducted an open-label, single-center, multicohort, prospective study. Patients were women with pathologically and immunohistochemically confirmed HR-positive/HER-2-negative patients with advanced breast cancer. Patients relapsed during or after adjuvant endocrine therapy or progressed after completing at least one previous line of treatment for advanced breast cancer. Patients were assigned to four parallel treatment cohortsmatched to mutations identified in ctDNA: 1) cohort A comprised patients with abnormal activation of PI3K/Akt/mTOR pathway signal, preferred mTOR inhibitor combined with endocrine therapy; 2) cohort B comprised patients with ESR1 mutation and who did not use fulvestrant before, preferred fulvestrant; 3) cohort C comprised patients with HER2 mutations, preferred pyrotinib combined with endocrine therapy; 4) cohort D comprised patients with no significant gene mutation, making treatment plan according to the actual clinical situation. If more than one mutation was identified, the priority of entry is cohorts C, cohorts A and cohort B. In the A-D cohort, patients who obey the treatment plan are the compliance group, and patients who do not obey the treatment plan are the violation group. The primary endpoints were progression-free survival (PFS), and the secondary endpoints included overall survival time (OS). Results: A total of 113 patients underwent NGS detection of ctDNA, and 84 patients were enrolled in the study. In all cohorts, combined median PFS was 4.9 months, and the median PFS in the compliance group was 3.0 months longer than in the violation group (6.03 vs 3.03 months, p = 0.0222, HR = 0.5743, 95%CI 0.3273-1.007). In cohort C, the median PFS was 11.1 months in the compliance group and 2.22 months in the violation group (p = 0.0067, HR = 0.1980, 95%CI 0.032-1.22). There was no significant difference in the median PFS between patients with and without compliance with the treatment protocol in cohort A and cohort B (p = 0.5054 and 0.7325, respectively). Conclusions: The study suggested that ctDNA detection may guide the optimal endocrine therapy strategy for patients with advanced breast cancer and achieve the benefit of progression free survival. NGS detection might distinguish patients with HER2 mutation and provide new treatment strategies. Clinical trial information: NCT03786575.
A comparison of the PLUM and RPCRC- MRI-based prostate cancer risk prediction models in two North American and European cohorts
Authors: S. Remmers, H.D. Patel, G. Rac, M.J. Roobol, A.M. Fang, P. Davik, S. Rais-Bahrami, G.N. Gupta
Journal: European Urology (2022)
Identification of a distinct NK-like hepatic T-cell population activated by NKG2C in a TCR-independent manner
Authors: June-Young Koh, Min-Seok Rha, Seong Jin Choi, Ha Seok Lee, Ji Won Han, Heejin Nam, Dong-Uk Kim, Jae Geun Lee, Myoung Soo Kim, Jun Yong Park, Su-Hyung Park, Dong Jin Joo, Eui-Cheol Shin
Journal: Journal of Hepatology (2022)

The liver provides a unique niche of lymphocytes enriched with a large proportion of innate-like T cells. However, the heterogeneity and functional characteristics of the hepatic T-cell population remain to be fully elucidated.We obtained liver sinusoidal mononuclear cells from the liver perfusate of healthy donors and recipients with HBV-associated chronic liver disease (CLD) during liver transplantation. We performed a CITE-seq analysis of liver sinusoidal CD45+ cells in combination with T cell receptor (TCR)-seq and flow cytometry to examine the phenotypes and functions of liver sinusoidal CD8+ T cells.We identified a distinct CD56hiCD161-CD8+ T-cell population characterized by natural killer (NK)-related gene expression and a uniquely restricted TCR repertoire. The frequency of these cells among the liver sinusoidal CD8+ T-cell population was significantly increased in patients with HBV-associated CLD. Although CD56hiCD161-CD8+ T cells exhibit weak responsiveness to TCR stimulation, CD56hiCD161-CD8+ T cells highly expressed various NK receptors, including CD94, killer immunoglobulin-like receptors, and NKG2C, and exerted NKG2C-mediated NK-like effector functions even in the absence of TCR stimulation. In addition, CD56hiCD161-CD8+ T cells highly respond to innate cytokines, such as IL-12/18 and IL-15, in the absence of TCR stimulation. We validated the results from liver sinusoidal CD8+ T cells using intrahepatic CD8+ T cells obtained from liver tissues.In summary, the current study found a distinct CD56hiCD161-CD8+ T-cell population characterized by NK-like activation via TCR-independent NKG2C ligation. Further studies are required to elucidate the roles of liver sinusoidal CD56hiCD161-CD8+ T cells in immune responses to microbial pathogens or liver immunopathology.The role of different immune cell populations in the liver is becoming an area of increasing interest. Herein, we identified a distinct T-cell population that had features similar to those of natural killer (NK) cells - a type of innate immune cell. This distinct population was expanded in the livers of patients with chronic liver disease and could thus have pathogenic relevance.
Analysis of Comorbidities, Clinical Outcomes, and Parathyroidectomy in Adults With Primary Hyperparathyroidism
Authors: Kristian F. Axelsson, Märit Wallander, Helena Johansson, Nicholas C. Harvey, Liesbeth Vandenput, Eugene McCloskey, Enwu Liu, John A. Kanis, Henrik Litsne, Mattias Lorentzon
Journal: JAMA Network Open (2022)

<h3>Importance</h3> Patients with primary hyperparathyroidism (pHPT) appear to have an increased risk of fractures and other comorbidities, such as cardiovascular disease, although results from previous studies have been inconsistent. Evidence of the association of parathyroidectomy (PTX) with these outcomes is also limited because of the lack of large well-controlled trials. <h3>Objective</h3> To investigate whether untreated pHPT was associated with an increased risk of incident fractures and cardiovascular events (CVEs) and whether PTX was associated with a reduced risk of these outcomes. <h3>Design, Setting, and Participants</h3> This cohort study included all patients who were diagnosed with pHPT at hospitals in Sweden between July 1, 2006, and December 31, 2017. Each patient was matched with 10 control individuals from the general population by sex, birth year, and county of residence. The patients were followed up until December 31, 2017. Data analyses were performed from October 2021 to April 2022. <h3>Main Outcomes and Measures</h3> The primary outcomes were fractures, CVEs, and death. Cumulative incidence of events was estimated using the 1-minus Kaplan-Meier estimator of corresponding survival function. Cox proportional hazards regression models were used to calculate hazard ratios (HRs). <h3>Results</h3> A total of 16 374 patients with pHPT were identified (mean [SD] age, 67.5 [12.9] years; 12 806 women [78.2%]), with 163 740 control individuals. The follow-up time was 42 310 person-years for the pHPT group and 803 522 person-years for the control group. Compared with the control group, the pHPT group had a higher risk of any fracture (unadjusted HR, 1.39; 95% CI, 1.31-1.48), hip fracture (unadjusted HR, 1.51; 95% CI, 1.35-1.70), CVEs (unadjusted HR, 1.45; 95% CI, 1.34-1.57), and death (unadjusted HR, 1.72; 95% CI, 1.65-1.80). In a time-dependent Poisson regression model, PTX was associated with a reduced risk of any fracture (HR, 0.83; 95% CI, 0.75-0.93), hip fracture (HR, 0.78; 95% CI, 0.61-0.98), CVEs (HR, 0.84; 95% CI, 0.73-0.97), and death (HR, 0.59; 95% CI, 0.53-0.65). <h3>Conclusions and Relevance</h3> Results of this study suggest that pHPT is associated with increased risk of fractures, CVEs, and death, highlighting the importance of identifying patients with this condition to prevent serious unfavorable outcomes. The reduced risk of these outcomes associated with PTX suggests a clinical benefit of surgery.
Oncological results of cytoreductive partial nephrectomy in mRCC patients
Authors: I. Vitruk, S. Semko, O. Voylenko, M. Pikul, O. Stakhovskyi, O. Kononenko, B. Hrechko, D. Koshel, A. Tymoshenko, E. Stakhovsky
Journal: European Urology (2022)
SURG-09. Hypothalamic involvement in pediatric craniopharyngiomas;how to define and to realize optimal neurosurgical resections
Authors: Eelco Hoving, Kirsten van Baarsen, Jiska van Schaik, Hanneke van Santen
Journal: Neuro-Oncology (2022)

Abstract The optimal neurosurgical strategy for pediatric craniopharyngiomas is on debate with shifts from gross total resection to limited resections in combination with local radiotherapy. The most relevant question underlying this ongoing discussion is how to prevent additional surgical morbidity to the hypothalamus. Limited neurosurgical resection in combination with local radiotherapy has been proved a safe alternative to gross total resection concerning tumor control. Pre-operative anatomical grading of hypothalamic involvement has been proposed by Puget et al using MRI discriminating between no hypothalamic involvement (grade 0), hypothalamic displacement (grade 1), and hypothalamic disruption (grade 2). Subsequently, post-operative hypothalamic damage can also be assessed on post-op MRI by the grading of the Vile et al in no discernable damage (grade 0), abnormality of floor of third ventricle (grade 1), or damaged or deficient floor of third ventricle (grade 2). Three questions remain to be settled: 1. How to define pre-operatively the extent of resection 2. How to realize per-operatively the intended limited resection, and three. How to determine post-operatively the (additional) surgical damage to the hypothalamus. We retrospectively evaluated a series of 25 children with craniopharyngioma being resected in our center from June 2018 until January 2022, with pre- and post-operative grading of hypothalamic involvement. In total 11 patients were downgraded on the post-operative compared to the pre-operative scale; either by 1 grade (n=6) or by 2 grades (n=5). These findings illustrate that the preoperative grading score does not always represent the actual hypothalamic involvement. This complicates the definition of limited surgery pre-operatively and illustrates the importance of both how to integrate per-operative findings in the realization of the intended limited resection and how to evaluate hypothalamic damage caused by tumor growth versus neurosurgical intervention. A more detailed treatment algorithm will be discussed.
The Visayan Warty Pig (<i>Sus cebifrons</i>) Genome Provides Insight Into Chromosome Evolution and Sensory Adaptation in Pigs
Authors: Langqing Liu, Hendrik-Jan Megens, Richard P.M.A. Crooijmans, Mirte Bosse, Qitong Huang, Linda van Sonsbeek, Martien A.M. Groenen, Ole Madsen
Journal: Molecular Biology and Evolution (2022)

It is largely unknown how mammalian genomes evolve under rapid speciation and environmental adaptation. An excellent model for understanding fast evolution is provided by the genus Sus, which diverged relatively recently and lacks postzygotic isolation. Here, we present a high-quality reference genome of the Visayan warty pig, which is specialized to a tropical island environment. Comparing the genome sequences and chromatin contact maps of the Visayan warty pig (Sus cebifrons) and domestic pig (Sus scrofa), we characterized the dynamics of chromosomal structure evolution during Sus speciation, revealing the similar chromosome conformation as the potential biological mechanism of frequent postdivergence hybridization among Suidae. We further investigated the different signatures of adaptive selection and domestication in Visayan warty pig and domestic pig with specific emphasize on the evolution of olfactory and gustatory genes, elucidating higher olfactory diversity in Visayan warty pig and positive and relaxed evolution of bitter and fat taste receptors, respectively, in domestic pig. Our comprehensive evolutionary and comparative genome analyses provide insight into the dynamics of genomes and how these change over relative short evolutionary times, as well as how these genomic differences encode for differences in the phenotypes.
Efficacy of lurbinectedin in a clinical trial versus other standard of care in a real-world comparator arm in relapsed/refractory small cell lung cancer patients.
Authors: Apar Kishor Ganti, Patricia Prince, Xue Wang, Adina Estrin, Anne Boccuti, Badri Rengarajan, Navit Naveh, Ralph D'Agostino, Trevor Alvord, Rami Ben-Joseph
Journal: Journal of Clinical Oncology (2022)

e20619 Background: Lurbinectedin monotherapy is currently approved for the treatment of adult patients with metastatic small cell lung cancer (SCLC) with disease progression on or after platinum-based chemotherapy based on the results of a single-arm phase 2 basket trial. The current study established real-world comparator arms (RWCAs) to enable retrospective comparison of the efficacy of lurbinectedin from the trial, notably overall survival (OS) and overall response rate (ORR), to other standard of care treatments. Methods: This exploratory study consisted of two arms, where the 1 st arm was the lurbinectedin trial arm (LTA) comprised of data from the SCLC cohort of the trial (NCT02454972) and the 2 nd arm was an RWCA sourced from ConcertAI electronic medical records in the US (2010 to 2019). Relevant inclusion and exclusion criteria from the trial were applied to the RWCA to ensure comparability at baseline. Given the absence of Eastern Cooperative Oncology Group performance status (ECOG) for a sizable portion of patients in the RWCA, two RWCA groups were studied, one that excluded patients with reported ECOG &gt; 2 (RWCA1) and the other that excluded patients with reported ECOG &gt; 2 and missing ECOG (RWCA2). Propensity score (PS) weighting was used to further balance measured baseline characteristics between LTA and each RWCA. OS was defined as the time from treatment initiation to death. Weighted cox regression was used to compare OS. ORR was defined as the percentage of patients with a complete or partial response. A weighted two-sample test of proportions was used to compare ORR. Results: This study included 105 patients in LTA and 121 in RWCA1 (74 in RWCA2). After PS weighting, baseline characteristics were mostly similar between LTA and each RWCA. ECOG was balanced between RWCA2 and LTA but was different between RWCA1 and LTA. A numerical median OS benefit of 3.8 and 4.7 months was observed in LTA, compared to RWCA1 and RWCA2, respectively (see table). Probability of survival was greater in LTA compared to RWCAs at 3 and 6 months. ORR was two-fold higher in LTA compared to RWCA1. Consistent findings were seen for LTA compared to RWCA2. Conclusions: Lurbinectedin monotherapy demonstrated improved median OS, lower risk of death at 3 and 6 months, and higher response rate compared to other standard of care treatments in relapsed/refractory SCLC. Future studies with larger sample size powered to detect statistical differences in OS are warranted.[Table: see text]
Interaction effect between NAFLD severity and high carbohydrate diet on gut microbiome alteration and hepatic <i>de novo</i> lipogenesis
Authors: Hyena Kang, Hyun Ju You, Giljae Lee, Seung Hyun Lee, Taekyeong Yoo, Murim Choi, Sae Kyung Joo, Jeong Hwan Park, Mee Soo Chang, Dong Hyeon Lee, Won Kim, GwangPyo Ko
Journal: Gut Microbes (2022)

Nonalcoholic fatty liver disease (NAFLD) is associated with high carbohydrate (HC) intake. We investigated whether the relationship between carbohydrate intake and NAFLD is mediated by interactions between gut microbial modulation, impaired insulin response, and hepatic de novo lipogenesis (DNL). Stool samples were collected from 204 Korean subjects with biopsy-proven NAFLD (n = 129) and without NAFLD (n = 75). The gut microbiome profiles were analyzed using 16S rRNA amplicon sequencing. Study subjects were grouped by the NAFLD activity score (NAS) and percentage energy intake from dietary carbohydrate. Hepatic DNL-related transcripts were also analyzed (n = 90). Data from the Korean healthy twin cohort (n = 682), a large sample of individuals without NAFLD, were used for comparison and validation. A HC diet rather than a low carbohydrate diet was associated with the altered gut microbiome diversity according to the NAS. Unlike individuals from the twin cohort without NAFLD, the abundances of Enterobacteriaceae and Ruminococcaceae were significantly different among the NAS subgroups in NAFLD subjects who consumed an HC diet. The addition of these two microbial families, along with Veillonellaceae, significantly improved the diagnostic performance of the predictive model, which was based on the body mass index, age, and sex to predict nonalcoholic steatohepatitis in the HC group. In the HC group, two crucial regulators of DNL (SIRT1 and SREBF2) were differentially expressed among the NAS subgroups. In particular, kernel causality analysis revealed a causal effect of the abundance of Enterobacteriaceae on SREBF2 upregulation and of the surrogate markers of insulin resistance on NAFLD activity in the HC group. Consuming an HC diet is associated with alteration in the gut microbiome, impaired glucose homeostasis, and upregulation of hepatic DNL genes, altogether contributing to NAFLD pathogenesis.
Anti-cancer effects of high-dose selenium via lipid peroxidation in ovarian cancer.
Authors: Jung-A Choi, Elizabeth Hyeji Lee, Hyosun Kim, Hanbyoul Cho, Jae-Hoon Kim
Journal: Journal of Clinical Oncology (2022)

e17547 Background: Selenium is an essential trace element and act as a regulator in the oxidation-reduction system. Selenium deficiency is observed in various cancers. Therefore, we investigated the relevance of high-dose selenium with the anticancer effect of ovarian cancer. Methods: We evaluated cytotoxicity and cell death by MTT assay and Annexin V-FITC/PI-labeled flow cytometry and biological function by invasion assay, ROS assay, immunoblotting, and FACS analysis. Using SKOV3-bearing xenograft mouse models, we evaluated the anti-cancer effect of high-dose selenium. Selenium toxicity was evaluated by the amount of ALT, AST, BUN and creatinine in the serum of C57BL/6 mice. Results: We observed that high-dose selenium, which was exposed to ovarian cancer cells, significantly increases the generation of reactive-species oxygen (ROS), leading to more significant cell death and cytotoxicity compared to low doses. We found that high-dose selenium triggers lipid peroxidation-mediated cell deaths and causes a reduction of glutathione peroxidase (GPX) systems. As a result of examining the lethal dose of selenium to the C57BL/6 nude mouse, it occurred in the concentration range of 3000 μg/Kg or more. SKOV3-bearing mouse models revealed the high-dose selenium administration (2000 μg/Kg) significantly reduced the ovarian tumor growth (p &lt; 0.05). Moreover, we confirmed that high-dose selenium inhibited the expression of increased GPX in SKOV3-bearing mice. Conclusions: Our results suggest that high-dose selenium induces an anticancer effect through lipid peroxidation regulation according to the GPX redox system. Furthermore, we can suggest that chemotherapy based on high-dose selenium may have the effect of maximizing therapeutic efficacy and reducing anticancer drug resistance in ovarian cancer.